Is CDKL5 p.Pro180Ser (c.538C>T) pathogenic?

CDKL5 p.Pro180Ser (c.538C>T) is classified Likely pathogenic in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-15). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CDKL5 p.Pro180Ser (c.538C>T)?

CDKL5 p.Pro180Ser (c.538C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CDKL5 p.Pro180Ser (c.538C>T) in the general population?

CDKL5 p.Pro180Ser (c.538C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Pro180Ser (c.538C>T)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

CDKL5 p.Pro180Ser

c.538C>T · rs2518853590 · VCV1747213

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic ✓ concordant with ClinVar · top 4% in CDKL5
REVEL	0.862	moderately pathogenic-leaning
SaProt	LLR -14.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKL5
Protein: p.Pro180Ser
Coding: c.538C>T
MANE Select: NM_001323289
dbSNP: rs2518853590
Type: single nucleotide variant
Location: chrX:18584337 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 180: the protein kinase domain; a UniProt-annotated variant site (in dee2); an α-helix

Full CDKL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RS1 p.Ser180Leu Uncertain significance ★★ ⚠ same residue
RS1 p.Ser180= Likely benign ★ same residue
RS1 p.Ser180Pro Pathogenic same residue
CDKL5 c.2152+1G>A Pathogenic ★★ same condition
CDKL5 p.Gln605Ter Pathogenic ★★ same condition
CDKL5 p.Gln69Ter Pathogenic ★★ same condition
CDKL5 p.Gln865Ter Pathogenic ★★ same condition
CDKL5 p.Ala166Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdkl5-p-pro180ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown